The bond at the heart of the work is the C(sp3)–C(sp3) linkage, the connection between two tetrahedral, saturated carbon atoms. These bonds form the skeletal framework of the vast majority of drugs, agrochemicals and natural products, yet they remain among the hardest bonds for synthetic chemists to forge selectively. Conventional cross-coupling methods, which earned the Nobel Prize in Chemistry in 2010, excel at joining flat, sp2-hybridized carbons but struggle with the stubborn, unreactive sp3 carbons that dominate three-dimensional molecular architecture. Radical approaches — in which two carbon-centred radicals recombine — offer an appealing alternative, but they come with a fundamental catch.

That catch is diffusion control. When two free radicals meet in solution, they combine at essentially the rate at which random molecular motion brings them together. The chemistry offers no inherent preference for coupling two different radicals over two identical ones, so reactions tend to produce statistical mixtures: the desired cross-coupled product alongside wasteful homodimers of each partner. Compounding the problem, the transition-metal catalysts typically used to impose order on this chaos are exquisitely sensitive to the redox environment of the reaction. Radical generation is inherently a redox process, and the reactive intermediates it creates can push a delicate nickel or iron catalyst into inactive oxidation states, collapsing the very selectivity the catalyst is meant to provide.

The Harbin team’s solution is an elegant act of chemical bookkeeping: decoupling radical generation from catalytic redox maintenance. Instead of asking a single catalytic system to both create radicals and keep the cross-coupling catalyst in its productive state, the researchers split the labour. Light handles the first job through photoinduced ligand-to-metal charge transfer, a process in which a photon excites an electron from a ligand — here, a carboxylate or alkoxide bound to an iron centre — up to the metal, tearing the bond apart and releasing an alkyl radical under remarkably mild conditions. Electricity handles the second job, continuously regulating the redox balance of the catalytic cycle through the applied potential at the electrode, so that the metal catalyst neither accumulates in an over-reduced state nor burns out through over-oxidation.

Bringing these two energy inputs together with a dual-metal catalyst — iron for radical generation and nickel for selective bond formation — the system accomplishes an impressive range of transformations. Double decarboxylative couplings join two carboxylic acids by expelling carbon dioxide from both partners. Dehydroxymethylative couplings convert alcohols into alkyl radicals by cleaving a C–C bond adjacent to the hydroxyl group. Deformylative couplings do the same for aldehydes, stripping the formyl group to reveal the underlying alkyl fragment. In every case, the starting materials are native functional groups — the very handles already present in feedstock chemicals, metabolites and drug candidates — requiring no conversion into redox-active esters or other activated derivatives.

The substrate scope reported in the study is strikingly broad. The method accommodates primary, secondary and even sterically hindered tertiary carbon centres, and it works across every pairing: primary-to-primary, primary-to-secondary, secondary-to-secondary, primary-to-tertiary and even tertiary-to-tertiary couplings. Quaternary carbon centres — carbons bonded to four other carbons, a structural motif that confers biological potency but that synthetic chemists find notoriously difficult to construct — fall within reach. The authors also demonstrated applications to the synthesis of pharmaceutically relevant intermediates, suggesting the chemistry could shorten routes to drug candidates by allowing medicinal chemists to couple molecular fragments at late stages rather than building complex scaffolds from scratch.

How does the system avoid the statistical chaos that plagues ordinary radical recombination? The mechanistic studies point to a process called SH2 radical sorting, or bimolecular homolytic substitution at a metal centre. Rather than letting two radicals find each other freely in solution, the nickel catalyst captures one radical to form a high-valent organonickel species, and the second radical then attacks that complex directly, displacing the coupled product in a single, ordered step. This pathway imposes selectivity that diffusion-controlled recombination cannot, channelling the reaction toward the cross-coupled product. Electron paramagnetic resonance spectroscopy and cyclic voltammetry provided experimental support for this picture, tracking the radical intermediates and the oxidation states of the nickel catalyst as the reaction proceeded.

One of the most intriguing mechanistic findings concerns a seemingly humble additive: a sacrificial alkyl bromide. Mechanistic analysis indicated that this reagent prevents over-reduction of nickel, sustaining a Ni(II)/Ni(III) catalytic cycle — the oxidation-state shuttle that mediates the selective radical cross-coupling. In an electrochemical setting, where the electrode continuously pumps electrons into the system, keeping the catalyst from sliding into an inactive low-valent state is a genuine challenge. The sacrificial bromide acts as a redox buffer, preferentially accepting electrons that would otherwise reduce the nickel catalyst beyond its productive cycle. It is a small molecular chaperone with an outsized role in keeping the entire catalytic machine running.

The significance of the work extends beyond any single reaction. It sits at the confluence of three rapidly advancing fields: photocatalysis, electrocatalysis and first-row transition-metal catalysis. By using earth-abundant iron and nickel rather than precious metals, and by drawing energy from light and electricity rather than stoichiometric chemical oxidants and reductants, the approach aligns with the growing demand for sustainable synthesis. The electrochemical component also offers something batch chemistry rarely can: a tunable dial. By adjusting the applied potential, chemists can influence which intermediates form and which oxidation states persist, effectively programming the reaction’s selectivity through waveform control — a concept that has already transformed related electrochemical transformations such as modern versions of the century-old Kolbe electrolysis.

For the broader chemistry community, the study offers a template for taming radical reactions that were previously considered too promiscuous to be useful. If two carbon radicals can be generated from the most ordinary functional groups and then sorted selectively into a single cross-coupled product under mild conditions, the retrosynthetic imagination of chemists expands considerably: complex molecules could be conceived as combinations of simple carboxylic acid, alcohol or aldehyde fragments, joined where needed by a photon, an electron and a pair of cheap metal catalysts. The Harbin team’s data, including raw NMR, cyclic voltammetry and EPR datasets deposited openly on Zenodo, will allow other groups to scrutinize and build upon the mechanism. What remains to be seen is how far the platform can stretch — whether it can be rendered enantioselective, extended to heteroatom-bearing fragments, and scaled from milligram demonstrations to the gram and kilogram quantities that industrial synthesis demands. For now, the message is clear: the once-chaotic world of radical coupling is being brought under disciplined control, one photon and one electron at a time.

Subject of Research: Photoelectrochemical C(sp3)–C(sp3) radical cross-coupling of native functional groups using iron–nickel dual catalysis

Article Title: Photoelectrochemical C(sp3)–C(sp3) cross-coupling using native functional groups

Article References: Zhong, P.-F., Yang, C., Guo, L., & Xia, W. (2026). Photoelectrochemical C(sp3)–C(sp3) cross-coupling using native functional groups. Nature Synthesis. https://doi.org/10.1038/s44160-026-01162-w

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01162-w

Keywords: photoelectrochemistry, cross-coupling, C(sp3)–C(sp3) bonds, radical sorting, nickel catalysis, iron catalysis, ligand-to-metal charge transfer, decarboxylation, SH2 mechanism, electrocatalysis, photocatalysis, organic synthesis

The new method, developed by Chengmi Huang, Dong Wu, Shiyang Wang, Yangyang Li and Guoyin Yin in the laboratory of Guoyin Yin, with computational contributions from Shuang Deng and Xiaotian Qi, is a sequential three-component coupling of alkynes, organohalides and a diboron reagent. Alkynes are attractive building blocks because they are flat, linear and readily available, and their conversion into substituted alkenes by adding two different groups across the triple bond, a process known as difunctionalization, is a powerful way to generate molecular complexity in a single operation. The difficulty has always been control: which group adds to which end of the alkyne, and whether the two groups end up on the same side or opposite sides of the resulting double bond.

Traditional approaches to alkyne difunctionalization typically rely on predesigned substrates bearing directing groups, or on rigid, single-pathway reaction mechanisms that lock in one regiochemical and stereochemical outcome. That rigidity restricts structural diversity, forcing chemists to redesign substrates and conditions every time a different isomer is needed. The Wuhan team’s solution is conceptually different. Instead of fixing the pathway, they exploit the fact that nickel catalysts can operate through two fundamentally different reactive intermediates, organometallic species on one hand and free radicals on the other, and they show that the choice of ligand determines which of these pathways dominates.

Mechanistic studies, combining experiments with density functional theory calculations, revealed the heart of the switch. The electronic properties of the ligand regulate whether the nickel catalyst generates an organometallic intermediate or a radical intermediate after oxidative addition of the organohalide. When the organometallic pathway prevails, the reaction proceeds through a well-defined nickel-carbon bond and delivers one set of alkene products; when radical generation dominates, the reaction follows an entirely different trajectory. Remarkably, the team found that the intrinsic metal-binding ability of the various radicals further modulates their reactivity, providing a second layer of selectivity control that governs how the radical interacts with the nickel-bound alkyne.

This dual-control architecture allows the researchers to access alkene products that are otherwise difficult to make. Under one set of conditions, the coupling delivers uncommon 1,2-trans alkenes, in which the two newly installed groups sit on opposite carbons of the double bond and point away from each other. Under another set of conditions, the same three components combine to give 2,1-cis alkenes, with the groups on adjacent carbons and on the same face. Achieving both regioselectivity and unique stereoselectivity simultaneously in a single catalytic operation is rare, and the fact that the outcome can be toggled by ligand choice rather than by rebuilding the substrate is what makes the system genuinely programmable.

The programmability extends beyond stereochemistry into molecular homologation. By controlling the incorporation of two alkyne units into the product, the team accomplished the divergent synthesis of conjugated diene homologues, molecules that differ by the number of conjugated alkene units in their backbone. Conjugated dienes are ubiquitous structural motifs: they appear in natural products such as the sorbicillinoid family, in agrochemicals including neonicotinoid insecticides, and in functional materials where the extent of conjugation dictates optical and electronic properties. Being able to prepare two different conjugated diene homologues from the same reaction setup, choosing between them with the catalyst rather than with new starting materials, offers a modular route to libraries of these valuable compounds.

The concept of radical sorting has been gaining momentum in catalysis research in recent years. Landmark studies from the MacMillan group on alkene dialkylation by triple radical sorting, and from other laboratories on cross-couplings enabled by bimolecular homolytic substitution, have shown that selectively channelling different radical species through a catalytic cycle can enable transformations that would otherwise be hopelessly scrambled. The Wuhan work pushes this idea further by sorting not just among radicals but between radical and organometallic regimes, effectively giving the chemist a switch that selects the reactive personality of the catalyst. The authors’ computational analysis, including average local ionization energy mapping of nickel(I) intermediates and buried-volume steric maps of the ligand environment, provided a quantitative picture of how ligand electronics and sterics steer the competition between pathways.

Detailed mechanistic experiments underpinned the proposal. The team examined how different ligands altered the fate of the alkenyl-nickel and alkenyl-radical intermediates that arise after the first addition across the alkyne, and their calculations compared the competing pathways for two distinct ligand frameworks, designated L4 and L6, at a high level of theory in solvents matching the experimental conditions. The results showed that chemoselectivity, whether the intermediate continues down the productive coupling channel or diverts into an unproductive one, is dictated by the interplay of ligand electronics and the radical’s affinity for the metal centre. This mechanistic clarity is valuable in its own right, because it converts what could have been an empirical observation into a set of design principles that other laboratories can apply to their own catalytic problems.

The practical scope of the method was demonstrated across a broad collection of substrates, with crystallographic data for seven representative products deposited at the Cambridge Crystallographic Data Centre to confirm the assigned structures unambiguously. The authors also showcased synthetic applications, including downstream transformations of the borylated alkene products and an application to the synthesis of histamine H3 receptor inverse agonists, a class of pharmacologically active compounds, illustrating how the reaction could feed directly into medicinal chemistry workflows. Because the products carry a boronate handle, they are primed for further diversification through well-established organoboron chemistry, multiplying the value of each coupling event.

The work was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Shenzhen Science and Technology Program and institutional funds from Wuhan University, and it was peer reviewed by experts including Javier Corpas, Albert Poater and Qiuling Song. Beyond its immediate synthetic utility, the study signals a broader shift in how chemists think about selectivity. Rather than accepting the selectivity dictated by a substrate’s inherent bias, catalysts can now be engineered to override that bias and impose an outcome chosen by the operator. As switchable catalysis matures, the prospect of running a single reaction flask and extracting whichever molecular isomer a drug discovery or materials program requires, simply by swapping a ligand, moves from aspiration toward routine practice, and this nickel-catalysed alkene construction provides a compelling demonstration of that future.

Subject of Research: Ligand-switchable nickel catalysis for programmable regio-, stereo- and homologation-divergent construction of alkene skeletons from alkynes, organohalides and diboron reagents.

Article Title: Programmable alkene skeleton construction via switchable radical and organometallic sorting

Article References: Huang, C., Deng, S., Wu, D., Wang, S., Li, Y., Qi, X., & Yin, G. (2026). Programmable alkene skeleton construction via switchable radical and organometallic sorting. Nature Chemistry. https://doi.org/10.1038/s41557-026-02242-2

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02242-2

Keywords: nickel catalysis, alkyne difunctionalization, radical sorting, organometallic chemistry, alkene synthesis, conjugated dienes, stereoselectivity, regioselectivity, ligand control, diboron reagent, homologation, synthetic methodology